1,8-Ethano-5-oxo-octa- and -decahydroquinolines and mydriatic compositions thereof

ABSTRACT

Compounds of the general formula: ##STR1## wherein X is selected from the group consisting of oxygen, CH 2  and CH radicals, and when X designates oxygen, R designates alkyl, isoalkyl, aralkyl, and substituted aralkyl groups and when X designates CH 2  then R designates alkyl, phenyl or substituted phenyl group, and A-B is a single bond, and when X designates CH 2  R designates alkyl, phenyl or substituted phenyl groups and A-B is a double bond; and physiologically acceptable salts of these, and mydriatic pharmaceutical compositions containing the same as active ingredient.

This is a division of application Ser. No. 655,650 filed 2/2/76 now U.S.Pat. No. 4,083,985 issued 4/11/78.

SUMMARY OF THE INVENTION

The present invention relates to novel compounds of the general formula:##STR2## wherein X may be oxygen, CH₂ or CH; R may be alkyl, isoalkyl,phenyl and substituted phenyl groups, and when X is the CH₂ group thenA-B is a single bond, and when X is the CH group, then A-B is a doublebond.

Compounds defined above, wherein X designates ═0 comprise the fusedquinuclidine-valerolactone system, 6-oxa-1-azatricyclo(4.2,2.0²,7)-dodecan-5-one, alkylated congeners of these and salts ofsuch compounds. This comprises various stereo-isomers and opticallyactive isomers of such compounds and salts. These are of the generalformula: ##STR3## wherein R is as defined above.

Compounds defined above, wherein X designates ##STR4## or CH and whereinR designates phenyl or substituted phenyl or alkyl are of the formula##STR5## wherein there is an optional 6-7 double-bond, and R is alkyl,phenyl or substituted phenyl, the preferred compound being the onewherein R is ethyl or phenyl.

The present invention relates also to pharmaceutical preparationscomprising a compound or salt as defined above as active ingredient.

The term "alkyl" relates to groups such as methyl, ethyl, propyl, butyl;the term isoalkyl defines groups such as isopropyl, isobutyl; cycloalkyldefines groups such as cyclopentyl, cyclohexyl. Representative aryl orheteroaryl groups are phenyl or thienyl; substituted aryl designatessuch groups as chlorophenyl, methoxy phenyl, trifluoromethylphenyl andamino-phenyl, or N,N-substituted aminophenyl, where N,N- is diloweralkyl.

The invention comprises salts of the above, which are suitable forpharmaceutical or veterinary application, and also to salts useful inthe purification and crystallization of the novel compounds. Amongstsuch salts there may be mentioned the hydrochlorides, sulfates,methanesulfonates and salts with organic acids.

Amongst N-alkyl congeners there may be mentioned N-methyl, N-ethyl,N-benzyl compounds, especially in the form of the iodides, bromides orchlorides.

Starting compounds useful in the preparation of compounds (II) of thepresent invention of the 4-alkyl6-oxa-1-azatricyclo-(6.2.2.0²,7)dodecan-5-one type are mono-substituted esters of malonic acid, such asdiethyl methylmalonate, diethyl-ethylmalonate, diethyl propylmalonate,diethyl isopropylmalonate, diethyl n-butylmalonate,diethylbenzylmalonate and the like. Starting materials for thepreparation of 4-aryl-6-oxa-1-azaytricyclo (4.2.2.0²,7) dodecan-5-onetype compounds are ortho- metaand para-substituted esters ofphenylacetic acid, such as ethyl p-methylphenylacetate, ethylm-methoxyphenylacetate or substituted phenylacetonitriles, such asp-chlorophenyl-acetonitrile.

Compounds of the formula (III) are prepared in two steps by reacting2-methylene-quinuclidin-3-one and methyl benzylketone followed byselective catalytic reductions. ##STR6## or in three steps, bycondensation of 2-methylene-3-quinuclidinone with a substitutedethylacetoacetate, followed by decarboxylation and subsequent reduction,as set out in the following reaction scheme: ##STR7## The compoundsaccording to the present invention are valuable as active ingredients inpharmaceutical compositions of matter. They are valuable as drugs, inthe treatment and in the alleviation of the manifestations ofParkinson's diseases; they are effective general psychomotor stimulants,and as such they are of special value in geriatrics. The compounds ofthe present invention can be used as antimotion sickness drugs, they areof value in opthalmology as mydriatics. They can be used in smokingabstinence treatments inducing exaggerated effects of tobacco. Thecompounds of the present invention are effective "wake-up" agents, andas such they can be used to correct the depressant effect ofbarbiturates. They can be used to counter the effect of drowsiness ofantihistaminics and similar drugs.

They are also useful in the treatment of hyperkinesis in children, ofnarcolepsy, of mental depression of organic origin and of obesity.

The dosage is generally of about 10 mg to about 100 mg for an adult perday. The drugs according to the present invention can be given by way ofinjection in a suitable diluent or carrier, the drugs can be given peros, in the form of suppositories and by any other conventional manner ofapplication, such as infusion, etc.

The compounds of the present invention are of special value when used incombination with antihistminics to be used during day-time, as theresulting composition is devoid of the effect of drowsiness of theperson thus treated.

When applied for opthalmological use, the drugs of the present inventionare advantageously used in a conventional carrier or buffer. Theconcentrations can be varied according to the desired effect, and theywill be generally about 2 to 10% by weight of the active ingredient.

The present invention relates also to pharmaceutical and veterinarycompositions of matter comprising any of the novel compounds of theinvention, or combinations of any of these, as active ingredient.

The invention also relates to stereoisomers and optical isomers of thecompounds defined above, such isomers being due to the asymetry at thecarbon atoms in the 2-, 4- and 7-positions as defined above in therespective compounds (II), or in positions 2, 4 and 7 in compounds IIIwherein C₆ -C₇ is a single bond.

DESCRIPTION OF THE PREFERRED EMBODIMENT

The following examples are intended to illustrate the present inventionand these are to be construed in a non-limitative manner.

EXAMPLE 1

Ethanolic sodium ethoxide, previously prepared from 2.9 g of metallicsodium and 100 ml of ethanol, was added to diethyl methyl-malonate, 50g, and the mixture was refluxed for 30 min. then cooled to 5°. Asolution of 2-methylenequinuclidin-3-one, 39.4 g, in ethanol, 50 ml, wasthen added dropwise and with stirring. After 16 hrs. at roomtemperature, the resulting solution was neutralized with acetic acidthen subjected to evaporation at reduced pressure. Water, 100 ml wasadded and the mixture was extracted with chloroform. Evaporation of thissolvent gave diethyl (3-oxo quinuclidin-2-yl)-methyl-methylmalonate, 72g (81%), m.p., 58.4° (from petroleum ether). A solution of the foregoingcompound, 72 g, in ethanol, 50 ml, was treated at 5° and with stirringwith a solution of sodium borohydride, 3.55 g, in ethanol, 600 ml. Theborohydride solution was added in small increments over a period of sixhours. After 20 hours, the mixture was neutralized with concentratedhydrochloric acid, then subjected to evaporation at reduced pressure.The residue was taken up in 200 ml of water and extracted withchloroform. Evaporation of this solvent left a syrupy residue, 55 g,which consisted of the compound diethyl(3-hydroxyquinucldin-2-yl)methyl-methylmalonate; its methiodide salt,prepared with methyl iodide in acetone, has a m.p. of 228.2°.

The foregoing product, 54.8 g was refluxed with concentratedhydrochloric acid, 200 ml. and water, 100 ml for 20 hours. Partialevaporation of the solvent and cooling induced the crystallization of2-(trans-3-hydroxyquinuclidin2-yl)- methylpropanoic acid hydrochloride,8 g (18%), which is a by-product; m.p. 268.8°-269.4°. Furtherconcentration of the mother liquor and cooling provoked thecrystallization of the desired 4-methyl-6-oxa-1-azatricyclo (4.2.2.0²,7)dodecan-5-one hydrochloride, 27.5 g, (66%), m.p. 267.2° withdecomposition.

EXAMPLE 2

Ethyl phenylacetate, 49.2 g was added to a solution of sodium ethoxidepreviously prepared from metallic sodium, 2.9 g and ethanol, 100 ml. Themixture was cooled to 5°, then a solution of2-methylenequinuclidin-3-one, 39.4 g, in ethanol, 50 ml. was addeddropwise and with stirring. After 16 hours at room temperature, thesolution was neutralized with acetic acid then subjected to evaporationat reduced pressure. Water, 100 ml. was added to the residue and themixture was extracted with chloroform. Evaporation of this solvent gaveethyl (3-oxoquinuclidin-2-yl)methylphenylacetate, 54 g (60%); b.p.195°-200° at 1 mm Hg; m.p. of methiodide salt, 194.7°-195.6°.

The foregoing compound, 22.4 g was dissolved in ethanol, 100 ml, and theresulting solution was treated at 5° with a solution of sodiumborohydride 1.2 g in ethanol 200 ml. The borohydride solution was addedin small increments over a period of 6 hr. After 20 hr, the mixture wasneutralized with concentrated hydrochloric acid then subjected toevaporation at reduced pressure. The residue was taken up in 200 mlwater and extracted with chloroform. Evaporation of this solvent gaveEthyl (3-hydroxyquinuclidin-2-yl) methyl-phenylacetate, 19.5 g, (80%),m.p. 147.7°-148.2° after recrystallization from acetone.

The foregoing compound, 16.9 g, was refluxed in a mixture ofconcentrated hydrochloric acid, 100 ml and water, 40 ml for 20 hr.Evaporation of the solvent under reduced pressure left a glassy residuewhich was redissolved in water, 50 ml neutralized with sodiumbicarbonate and extracted with chloroform. Evaporation of this solventleft a residue which, when triturated with petrol ether, gavecrystalline 4-phenyl-6-oxa-1- azatricyclo (6.2.2.0²,7) dodecan-5-one,2.7 g (18%), m.p. 162°-163°.

By procedure similar to those described under the foregoing examples,analogous compounds may be prepared. A number of compounds thus preparedare given in the following list:

    __________________________________________________________________________    Compound                      m.p. or b.p.                                    __________________________________________________________________________    6-oxa-1-azatricyclo(6.2.2.O.sup.2,7)dodecan-5-one                                                           86.7°                                    4-methyl-6-oxa-1-azatricyclo (6.2.2.O.sup. 2,7)dodecan-5-one                                                102° 267.2°                       4-ethyl-6-oxa-1-azatricyclo(6.2.2.O.sup. 2,7)dodecan-5-one                                                  65° 255°-256°              4-isopropyl-6-oxa-1-azatricyclo(6.2.2.O.sup. 2,7)dodecan-5-one                                              130° 180.6°-182.7°         4-n-butyl-6-oxa-1-azatricyclo(6.2.2.O.sup. 2.7)dodecan-5-one                                                77.4°                                    4-benzyl-6-oxa-1-azatricyclo(6.2.2.O.sup. 2,7)dodecan-5-one                   hydrochloride                 282°(dec.) 159.6°-160.2.degree                                  .                                               4-p-methylphenyl-6-oxa-1-azatricyclo(6.2.2.O.sup. 2,7)dodecan-                5-one-hydrochloride           above 300° 143.1°-143.9.degree                                  .                                               4-p-chlorophenyl-6-oxa-1-azatricyclo(6.2.2 .sup.2,7)dodecan-                  5-one hydrochloride,          M.P.: above 300° C. 186.8°-187                                  .6°                                      4-m-methoxyphenyl-6-oxa-1-azatriclo(6.2.2.O.sup. 2,7)dodecan-                 5-one, free base,             M.P. 144.8° C.                           __________________________________________________________________________

The above boiling points are of the respective hydrochloride salts. Themethiodide salt of the salt compound in the above table melts at 158.1°C.

EXAMPLE 3 1-azatricyclo (6.2.2.0²,7)-4-phenyl dodecan-5-one,

The compound 1,4ethano-6-oxo-7-phenyl-1,2,3,4,6,7,8,8a-octahydroquinoline was prepared by a modification of the method ofOpenheimer and Bergmann, Synthesis 269 (1972) as follows:

To a solution prepared from 3 g sodium metal in 100 ml absolute methanolthere was added 45 g methyl benzyl ketone. The resulting solution wasrefluxed for 30 minutes, cooled to 0° C. and 39 g2-methylene-3-quinuolidinone was added. The solution was stirred atambient temperature during 48 hours, netralized by the addition of 3 mlacetic acid and the solvents were removed under reduced pressure. Therewas obtained a crude oil which was extracted with chloroform. Afterevaporation of the solvent there was obtained 52 g (a yield of 60%) ofthe desired product, M.P. from acetone, 125.7° C. Treatment withhydrochloric acid gave the corresponding hydrochloride salt, M.P. above300° C. (dec.).

The double bond in the above compound was subjected to selectivereduction by dissolving 15 g of the free base in 150 ml ethanol andreducing with hydrogen at 3 atmospheres in the presence of 0.5 g of 10percent palladium on carbon in a Parr apparatus. After 48 hours thesolution was filtered off and evaporated. The residue was recrystallizedfrom acetone, M.P.= 122.6° C. Treatment with gaseous hydrogen chloridein acetone gave the hydrochloride salt of 1-azatricyclo(6.2.2.0²,7)-4-phenyl dodecan-5-one-; of1,4-ethano-6-oxo-7-phenylperhydroquinoline in almost quantitative yield.M.P. above 300° C. (dec.).

EXAMPLE 4: 1-azatricyclo (6.2.2.0²,7)-4-ethyl dodecan-5-one.

The above compound was prepared by catalytic hydrogenation of the doublebond in 1,4-ethano6-oxo-7-ethyl-1,2,3,4,6,7,8,8a-octahydroquinoline by amodification of the method of and Bergmann Oppenheimer (see Ex.3). To asolution of 1 g sodium metal in 100 ml ethanol there was added 6.3 g-ethylacetoacetate. The resulting solution was refluxed during 30minutes, cooled to 0° C. and 5.5 g 2-methylene-3-quinuolidinone wasadded. The solution was stirred overnight at room temperature,neutralized with acetic acid and the solvents were evaporated. Theresidue was extracted with toluene which was subsequently removed. Theextract was treated with 17 ml concentrated hydrochloric acid and 5 mlof water under reflux during 7 hours. Evaporation of the solvent andtrituration with ethanol induced crystallization of the hydrochloridesalt of 1,4-ethano-6-oxo-7-ethyl-1,2,3,4,6,7,8,8 a-octahydroquinoline,M.P. above 300° C. (dec.). The free base, M.P.=63.5° C. may be purifiedby distillation under reduced pressure, B.P.,3mm Hg: 148° C. Yield: 60percent.

The double bond of the foregoing compound was selectively reduced asfollows: 10 gms. of the free base were dissolved in 100 ml ethanol; 0.5gm. of 10% palladium on carbon were added and the suspension was shakenunder hydrogen at 3 atmospheres in a Parr apparatus. After 48 hours, thesuspension was filtered and the clear filtrate was evaporated todryness. The residue consisted of 1-azatricyclo(6.2.2.O²,7)-4-ethyldodecan-5-one in almost quantitative yield. Themelting point of the hydrochloride salt is 291°-292.1°.

The compounds of the present invention of Formula III, wherein X is CH₂,have pharmacological properties analogous to the compounds of FormulaII, wherein X 15=0. They are of special value as psychomotor stimulants;they are effective antagonists against the depressant effects ofbarbiturates and prevent tremors in animals pretreated with oxotremorinethey are effective in a dosage range of 0.3 g. to 3.0 g. per kg. Sincetheir metabolism proceeds along pathways different from that of thecorresponding compounds having the valerolactone structure, they may beused in combination therapy, as adjuncts or synergists for each other inpharmaceutical preparations incorporating the two types of compounds.

ACUTE TOXICITY

The median lethal toxicity dosage of compounds of the present inventionwas determined by the procedure of Litchfield et al.,J.Pharmacol.Exp.Ther. 96, 39 (1949). In each experiment at least fivegroups of 6 mice each were used for each dosage and the LD₅₀ wasdetermined at 95 percent confidence limits.

Guinea Pig Ileum Test:

Peripheric antimuscarinic activity was assayed by the cummulative doseresponse procedure of Kuhnen-Clausen,Toxicol. App.Pharmacol. 23, 443(1972)

Oxotremorine Antagonism Test:

This was carried out according to Brinclecombe et al., J.Pharm.Pharmacl.23, 745-757 (1971).

An examination of compounds of the present invention has shown that themean median lethal dose of the hydrochloride salts in mice aftersubcutaneous injection in saline solution, is within the range of 75 mgto 273 mg/kg body weight. The most toxic compounds are those whereR=ethyl and the least toxic are those where R=phenyl.

The compounds are effective in preventing tremors induced in mice by theadministration of 200 micrograms oxotremorin per mouse(intraperitoneally). The median dosage for Compounds II and III whereinR=ethyl is 3 mg/kg by subcutaneous injection; taht of Compound II withR=phenyl is 6 mg/kg and for III with R=phenyl the dosage is 0.6 mg/kg.Thus, the therapeutic index for this particular effect is 25 to 50, and86 for the last mentioned compound. The equipotent molar ratio withrespect to atropine is 10 to 8, respectively. Compared with atropine,the peripheral anti-cholinergic effect of the compounds of the inventionis negligible. For example, the equipotent molar ratio in the preventionof contraction of the guinea pig ileum is: Atropine: 1: Compound II withR=ethyl: 7200; Compound II with R=phenyl: 9000; Compound III withR=ethyl: 1300; R=phenyl:1700. Thus, the central effect of the compoundsof the present invention is far more pronounced than their peripheraleffects. The ratio of central to peripheral activity for atropine is1:35, whereas the ratio for compounds of the present invention is 3: 1according to Inch et al., J.Phar.Phamacol. 25, 359 (1973).

Amongst other effects of compounds of the present invention there may bementioned rapid mydriasis on topical application of solutions to theeye. For example, a 2 percent solution to the eye of a rabbit resultedin an onset of mydriasis after 8 to 10 minutes, and the effect lastedfor about an hour. Injection into mice resulted in a slight hyperthermia(not exceeding +0.8° C.), and this reached a maximum after 20 minutes.Increased psychomotor activity was found with mice, evident from therate of rearing. A potentiation of the effect of nicotine was found uponapplication to the superior cervical ganglion of the cat. Fasciculationof striated muscle are induced only by very high doses, verging on themean lethal dose.

What is claimed is:
 1. A compound of the formula: ##STR8## wherein X isselected from the group consisting of CH₂ and CH, wherein when X is CH₂then A-B is a single bond and wherein when X is CH then A-B is a doublebond and wherein R is selected from the group consisting of lower alkyl,cyclopentyl, cyclohexyl, thienyl, phenyl, methylphenyl, methoxyphenyl,chlorophenyl, trifluoromethylphenyl, aminophenyl, di-loweralkylaminophenyl and benzyl, and physiologically acceptable salts thereof.
 2. Acompound of claim 1,1,8-ethano5-oxo-4-phenyl-1,10,9,8,5,4,3,2-octahydroquinoline and itsphysiologically acceptable salts.
 3. A compound of claim 1,1,8-ethano-5-oxo-4-phenyl-decahydroquinoline and its physiologicallyacceptable salts.
 4. A compound of claim 1,1,8-ethano-5-oxo-4-ethyldecahydroquinoline and its physiologicallyacceptable salts.
 5. A pharmaceutical preparation for use as amydriatic, comprising a mydriatic effective amount of the compound ofclaim 1 dissolved in a solvent therefor which is pharmaceuticallyacceptable therefor.